Indolinyl N-hydroxyurea and N-hydroxamic acid derivatives as lipoxygenase inhibitors

ABSTRACT

Certain indoline derivatives of the formula I: ##STR1## wherein the variables Y, A, R 1 , R 4  and n have the definitions set forth in the disclosure, have the ability to inhibit the 5-lipoxygenase enzyme. These compounds are useful in the treatment or alleviation of inflammatory diseases, allergic conditions and cardiovascular diseases in mammals and as the active ingredient in pharmaceutical compositions for treating such conditions.

This invention relates to novel N-hydroxyurea and hydroxamic acidcompounds. The compounds of the present invention inhibit the action oflipoxygenase enzyme and are useful in the treatment or alleviation ofinflammatory diseases, allergy and cardiovascular diseases in mammals,especially human subjects. This invention also relates to pharmaceuticalcompositions comprising such compounds.

BACKGROUND OF THE INVENTION

Arachidonic acid is known to be the biological precursor of severalgroups of endogenous metabolites, prostaglandins includingprostacyclins, thromboxanes and leukotrienes. The first step of thearachidonic acid metabolism is the release of arachidonic acid andrelated unsaturated fatty acids from membrane phospholipids, via theaction of phospholipase A2. Free fatty acids are then metabolized eitherby cyclooxygenase to produce the prostaglandins and thromboxanes or bylipoxygenase to generate hydroperoxy fatty acids which maybe furtherconverted to the leukotrienes. Leukotrienes have been implicated in thepathophysiology of inflammatory diseases, including rheumatoidarthritis, gout, asthma, ischemia reperfusion injury, psoriasis andinflammatory bowel diseases. Any drug that inhibits lipoxygenase isexpected to provide significant new therapy for both acute and chronicinflammatory conditions.

Recently several review articles on lipoxygenase inhibitors have beenreported. See H. Masamune and L. S. Melvin, Sr.: Annual Reports inMedicinal Chemistry, 24 (1989) pp 71-80 (Academic), and B. J.Fitzsimmons and J. Rokach: Leukotrienes and Lipoxygenases (1989) pp427-502 (Elsevier).

Compounds of similar structure to the object compounds of the presentinvention are disclosed in EP 279263 A2, WO 89/04299 and WO 91/16298.

The present inventors have worked to prepare compounds capable ofinhibiting the action of lipoxygenase and after extensive research theyhave succeeded in synthesizing a series of compounds as disclosed indetail herein.

SUMMARY OF THE INVENTION

The present invention provides novel N-hydroxyurea and hydroxamic acidderivatives of the following chemical formula (I) and pharmaceuticallyacceptable salts thereof; ##STR2## wherein R₁ is C₁ -C₄ alkyl or --NR₂R₃ ; R₂ and R₃ are each, independently, hydrogen or C₁ -C₄ alkyl; R₄ isC₃ -C₆ cycloalkyl, C₄ -C₇ cycloalkylalkyl, aryloxy C₂ -C₄ alkyl,arylthio C₂ C₄ alkyl, arylamino C₂ -C₄ alkyl, arylsulfinyl C₂ -C₄ alkyl,aryl, aryl C₁ -C₆ alkyl, aryloxyaryl C₁ -C₆ alkyl or arylthioaryl C₁ -C₆alkyl, and the aryl groups in the said aryloxyalkyl, arylthioalkyl,arylaminoalkyl, arylsulfinylalkyl, aryl, arylalkyl, aryloxyarylalkyl andarylthioarylalkyl may be substituted up to the maximal number ofsubstituents and the substituents are each, independently, selected fromthe group consisting of halo, cyano, C₁ -C₅ alkyl, C₂ -C₆ alkenyl, C₁-C₅ alkoxy, C₂ -C₆ alkenyloxy, C₂ -C₆ alkoxyalkyl, halosubstituted C₁-C₄ alkyl, halosubstituted C₁ C₄ alkoxy, C₂ -C₅ alkoxycarbonyl,aminocarbonyl and C₁ -C₄ alkylthio;

A is C₁ -C₆ alkylene, C₃ -C₆ alkenylene or --O--(CH₂)_(m) --;

Y is each, independently, halogen, halosubstituted C₁ -C₆ alkyl, C₁ -C₆alkyl, C₂ -C₆ alkenyl, C₁ -C₆ alkoxy or C₃ -C₈ alkenyloxy;

m is 2, 3 or 4;

n is 0, 1, 2 or 3;

and provided that the substituent Y, if present, and the linking group Aare attached to the aromatic ring.

DETAILED DESCRIPTION OF THE INVENTION

In this application,

the term "halo" is used herein to mean fluoro, chloro, bromo or iodo.

the term "alkyl" is used herein to mean straight or branched hydrocarbonchain radicals including, but not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, and the like;

the term "alkoxy" is used herein to mean --OR₅ (R₅ is alkyl) including,but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy andthe like;

the term "alkylthio" is used herein to mean --SR₆ (R₆ is alkyl)including, but not limited to, methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio and the like;

the term "alkenyl" is used herein to mean straight or branchedhydrocarbon chain radicals having one double bond including, but notlimited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1- and2-butenyl and the like;

the term "alkenyloxy" is used herein to mean --OR₇ (R₇ is alkenyl)including, but not limited to, ethenyloxy, 1- and 2-propenyloxy,2-methyl-1-propenyloxy, 1- and 2-butenyloxy and the like;

the term "alkylene" is used herein to mean optionally straight andbranched hydrocarbon chain spacer radicals including, such as --CH₂ --,--CH(CH₃)--, --CH₂ CH₂ --, --CH₂ CH(CH₃)--and the like;

the term "alkenylene" is used herein to mean straight or branchedhydrocarbon chain spacer radicals having one double bond including, suchas --CH═CH--, --CH═CHCH₂ --, --CH═CHCH(CH₃)--and the like;

the term "alkoxyalkyl" is used herein to mean --R₈ OR₉ (R₈ is alkyleneand R₉ is alkyl) including, but not limited to, methoxymethyl,ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl,isobutoxymethyl, t-butoxymethyl and the like;

the term "cycloalkyl" is used herein to mean cyclic hydrocarbon radicalsincluding, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like;

the term "cycloalkylalkyl" is used herein to mean an alkyl radical whichis substituted by cycloalkyl group including, but not limited to,cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyland the like;

the term "halosubstituted alkyl" refers to an alkyl radical as describedabove substituted with one or more halogens including, but not limitedto, chloromethyl, bromoethyl, trifluoromethyl and the like;

the term "halosubstituted alkoxy" is used herein to mean refers to analkoxy radical as described above substituted with one or more halogensincluding, but not limited to, chloromethoxy, bromoethoxy,difluoromethoxy, trifluoromethoxy and the like;

the term "alkoxycarbonyl" is used herein to mean --COOR₁₀ (R₁₀ is alkyl)including, but not limited to, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl and the like;

the term "aryl" is used herein to mean aromatic radicals including, butnot limited to, phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl,benzothienyl, benzofuryl and the like;

the term "arylene" is used herein to mean bivalent aromatic radicalsincluding, but not limited to, o-phenylene, m-phenylene and the like;

the term "arylalkyl" is used herein to mean an alkyl radical which issubstituted by aryl group including, but not limited to, benzyl,phenethyl, phenylpropyl, pyridylmethyl, thienylmethyl, furylmethyl andthe like;

the term "aryloxy" is used herein to mean --O--Ar₁ (Ar₁ is aryl)including, but not limited to, phenoxy, naphthoxy, pyridyloxy and thelike;

the term "arylthioalkyl" is used herein to mean --R₁₁ --S--Ar₂ (R₁₁ isalkylene and Ar₂ is aryl) including, but not limited to, phenylthioethyland the like;

the term "aryloxyalkyl" is used herein to mean --R₁₂ --O--Ar₃ (R₁₂ isalkylene and Ar₃ is aryl) including, but not limited to, phenyloxyethyl,pyridyloxypropyl and the like;

the term "arylsulfinylalkyl" is used herein to mean --R₁₃ --SO--Ar₄ (R₁₃is alkylene and Ar₄ is aryl) including, but not limited to,phenylsulfinylethyl, pyridylsulfinylpropyl and the like;

the term "arylaminoalkyl" is used herein to mean --R₁₄ --N(R₁₅)--Ar₅(R₁₄ is alkylene, R₁₅ is hydrogen or alkyl and Ar₅ is aryl) including,but not limited to, phenylaminoethyl, N-phenyl-N-methylaminoethyl andthe like;

the term "aryloxyarylalkyl" is used herein to mean --R₁₆ --Ar₆ --O--Ar₇(R₁₆ is alkyl, Ar₆ is arylene and Ar₇ are aryl) including, but notlimited to, phenoxybenzyl, pyridyloxyphenethyl and the like; and

the term "arylthioarylalkyl" is used herein to mean --R₁₇ --Ar₈ --S--Ar₉(R₁₇ is alkyl, Ar₈ is arylene and Ar₉ are aryl) including, but notlimited to, phenylthiobenzyl, pyridylthiophenethyl and the like.

General Synthesis

The compounds of formula (I) may be prepared by a number of syntheticmethods.

In one embodiment, compounds of the formula (IV) are prepared accordingto the reaction steps outlined in Scheme 1. ##STR3## where Q is:##STR4##

In the first step the diacetyl compound (III) is prepared by standardmethods known in the art. For example, the hydroxylamine (II) is reactedwith acetyl chloride or acetic anhydride in a reaction-inert solvent inthe presence of a suitable base. Preferred basic agents aretriethylamine and pyridine, however sodium hydride can be utilized.Suitable reaction-inert solvents include methylene chloride, chloroform,tetrahydrofuran, benzene and toluene. The reaction is usually carriedout in the temperature range of 0° C. through to ambient temperature.Reaction times of from 30 minutes to a few hours are common. The productcan be isolated and purified by conventional procedures, such as re,crystallization or chromatography.

The second step involves selective hydrolysis of (III) with anappropriate base. The basic agents suitably employed in this reactioninclude ammonia hydroxide, sodium hydroxide, potassium hydroxide andlithium hydroxide preferably in methanol, ethanol, isopropyl alcohol orwater, though binary solvent systems such as alcohol-water,tetrahydrofuran-water and the like may be employed. Reaction temperatureis usually in the temperature range of -10° C. through to ambienttemperature and the reaction is usually complete within a few minutes toseveral hours. The product of formula (IV) is isolated by standardmethods and purification can be achieved by conventional means, such asrecrystallization and chromatography.

In another embodiment, compounds of the formula (V) are prepared asillustrated in Scheme 2. ##STR5##

For example, the hydroxylamine (II) is treated with trimethylsilylisocyanate in a reaction-inert solvent usually at ambient through toreflux temperature to give the compound (V) in which R₂ and R₃ are bothhydrogen. Suitable solvents which do not react with reactants and/orproducts are, for example, tetrahydrofuran, dioxane, methylene chlorideor benzene. Similarly, N-hydroxy-N'-alkylurea compounds (R₂ is hydrogen,R₃ is alkyl) can be prepared by treating the hydroxylamine (II) with asuitable alkyl isocyanate in place of trimethylsilyl isocyanate. Analternative procedure employs treatment of (II) with gaseous hydrogenchloride in a reaction-inert solvent such as benzene or toluene and thensubsequent treatment with phosgene. Reaction temperatures are usually inthe range of ambient temperature through to boiling point of solvent.The intermediate carbamoyl chloride is not isolated but subjected to(i.e. in situ) reaction with aqueous ammonia, a primary amine (R₃ NH₂)or a secondary amine (R₂ R₃ NH). This gives compounds of formula (V),wherein R₂ and R₃ are each hydrogen, R₂ is hydrogen and R₃ is alkyl, R₂and R₃ are both alkyl, respectively. The product of formula (V) thusobtained is isolated by standard methods and purification can beachieved by conventional means, such as recrystallization andchromatography.

The aforementioned hydroxylamine (II) is easily prepared by standardsynthetic procedures from readily available carbonyl compound, i.e.ketone or aldehyde, or alcohol or halogen compound. For example,suitable carbonyl compound is converted to its oxime and then reduced tothe requisite hydroxylamine (II) with a suitable reducing agent (forexample, see R. F. Borch et at, J. Am. Chem. Soc., 93, 2897, (1971).Reducing agents of choice are, but not limited to, sodiumcyanoborohydride and borane complexes such as borane-pyridine,borane-triethylamine and boranedimethylsulfide, however triethylsilanein trifluoroacetic acid may also be employed.

Alternatively the hydroxylamine (II) can be prepared by treating thecorresponding alcohol with N,O-bis(tert-butyloxycarbonyl)hydroxylamineunder Mitsunobu-type reaction conditions followed by acid catalyzedhydrolysis of the N,O-protected intermediate product. N,O-Diacetylcompound (III) can be prepared employing N,O-diacetyl hydroxylamine inplace of N,O-bis(tert-butyloxycarbonyl)hydroxylamine thus providing aconvenient route to product of formula (III).

The aforementioned hydroxylamine (II) may also be prepared from suitablehalide compound by the reaction with O-protected hydroxylamine andsubsequent deprotection (see W. P. Jackson et. al., J. Med. Chem.,31,499, 1988). Preferred O-protected hydroxylamines are, but not limitedto, O-tetrahydropyranyl-, O-trimethylsilyl- and O-benzylhydroxylamine.

The requisite synthetic intermediate, carbonyl compound (ketone oraldehyde) is easily prepared by standard synthetic procedures from areadily available indoline compound. For example, a suitable indolinecompound is treated with Vilsmeier reagent or with suitable acidchloride or anhydride under Friedel Crafts reaction condition to give aformy- or alkylcarbonylindoline analog respectively. For typicalreaction condition, see Jerry March, Advanced Organic Chemistry, ThirdEd., pp 484-488 (1985).

Requisite synthetic intermediate, alcohol compounds are easily preparedby standard synthetic procedures from readily available carbonylcompound (eg. aldehyde, ketone or ester) by reduction with conventionalreducing agents such as NaBH₄, LiAlH₄, BH₃.THF complex and the like.

Some compounds having asymmetric center of the present invention arecapable of occurring in various stereoisomeric forms or configurations.Hence, the compounds can exist in separated (+)- and (-)-opticallyactive forms, as well as in racemic or (±)-mixtures thereof, and in thecase of those compounds with two or more asymmetric centers, they canadditionally exist as diastereomers with respective optical isomersthereof. The present invention is meant to include all such forms withinits scope. For instance, the diastereomers can be separated byfractional crystallization and the like, while the optically-activeisomers can be obtained by simply resolving the chemistry that are knownfor these purposes.

The pharmaceutically acceptable salts of the novel compounds of theinvention are readily prepared by contacting said compounds with astoichiometric amount of an appropriate metal hydroxide or alkoxide oramine in either aqueous solution or a suitable organic solvent. Therespective salts may then be obtained by precipitation or by evaporationof the solvent.

The compounds of this invention inhibit the activity of lipoxygenaseenzyme. This inhibition has been demonstrated by an assay using ratperitoneal cavity resident cells which determines the effect of saidcompounds on the metabolism of arachidonic acid.

All of the following examples 1 to 18 were tested according to themethods described in Jap. J. Inflammation 7: 145-150 (1987), "Synthesisof leukotrienes by peritoneal macropharges" and those were shown topossess the efficacy of inhibiting lipoxygenase activity.

In this test some preferred compounds indicated low IC₅₀ values, in therange of 0.01 to 30μM, with respect to lipoxygenase activity.

The ability of the compounds of the present invention to inhibitlipoxygenase enzyme makes them useful for controlling the symptomsinduced by the endogenous metabolites arising from arachidonic acid in amammalian subject, especially a human subject. The compounds aretherefore valuable in the prevention and treatment of such diseasestates in which the accumulation of arachidonic acid metabolites are thecausative factor; e.g. allergic bronchial asthma, skin disorders,rheumatoid arthritis, osteoarthritis and thrombosis.

Thus, the compounds of the present invention and their pharmaceuticallyacceptable salts are of particular use in the treatment or alleviationof inflammatory diseases in a human subject.

For treatment of the various conditions described above, the compoundsand their pharmaceutically acceptable salts can be administered to ahuman subject either alone, or preferably in combination withpharmaceutically acceptable careers or diluents in a pharmaceuticalcomposition according to standard pharmaceutical practice.

The compounds can be administered by various conventional routes of oraland parenteral administration and by inhalation. When the compounds areadministered orally, the dose range will be from about 0.1 to 20 mg/kgper body weight of the subject to be treated per day, preferably fromabout 0.1 to 1.0 mg/kg per day in single or divided doses. If parenteraladministration is desired, then an effective dose will be from about 0.1to 1.0 mg/kg per body weight of the subject to be treated per day. Insome instances it may be necessary to use dosages outside these limits,since the dosages will necessarily vary according to the age, weight andresponse of the individual patient as well as the severity of thepatient's symptoms and the potency of the particular compound beingadministered.

For oral administration, the compounds of the invention and theirpharmaceutically acceptable salts can be administered, for example, inthe form of tablets, powders, lozenges, syrups or capsules or as anaqueous solution or suspension. In the case of tablets for oral use,carriers which are commonly used include lactose and corn starch.Further lubricating agents such as magnesium stearate are commonlyadded. In the case of capsules, useful diluents are lactose and driedcorn starch. When aqueous suspensions are required for oral use, theactive ingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents can be added. Forintramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the active ingredient are usually prepared and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solute should be controlledto make the preparation isotonic.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples. Proton nuclear magnetic resonancespectra (NMR) were measured at 270 MHz unless otherwise indicated andpeak positions are expressed in parts per million (ppm) downfield fromtetramethylsilane. The peak shapes are denoted as follows: s-singlet,d-doublet, t-triplet, q-quartet, quint-quintet, m-multiplet, br-broad.

EXAMPLE 1 N-(1-Benzylindolin-5-yl)methyl-N-hydroxyurea ##STR6## (A)1-Benzyl-5-formylindoline,2

To a solution of indoline (2.8 ml, 25.2 mmol) in THF (60 ml) was added1.65N-n-BuLi (16 ml, 26.5 mmol) at -68° C. under a nitrogen atmosphereand the mixture was stirred for 35min. To the mixture was addedbenzylbromide (3.2 ml, 26.5 mmol) at -68° C. and the whole stirred at-68° C. for 15min and then allowed to stand at ambient temperature for 2hr. H₂ O (20 ml) was added and the mixture extracted with ethyl acetate(50 ml×2). The extracts were combined, washed with brine (50 ml×2),dried over MgSO₄ and evaporated in vacuo to give a light brown oil (1,5.16 g).

A solution of the product in DMF (13 ml) was added to a mixture of POCl₃(3.52 ml, 37.8 mmol) in DMF (38 ml) at room temperature and stirred for2 hr under a nitrogen atmosphere. H₂ O (20 ml) was added and the wholeconcentrated in vacuo. The resulting residue was extracted with ethylacetate (50 ml×3) and the extracts were combined, washed with saturatedNaHCO₃ solution (50 ml) and brine (50 ml), dried over MgSO₄ andevaporated in vacuo. Chromatography on silica gel (80 g) eluted withhexane/ethyl acetate (4:1) to give a light yellow oil (2, 2.82 g, 47.2%yield). NMR (CDCl₃) δ: 9.68 (s, 1H), 7.53-7.60 (m, 2H), 7.27-7.41 (m,5H), 6.47 (d, J=8.1 Hz, 1H), 4.42 (s, 2H), 3.58 (t, J=8.6 Hz, 2H), 3.08(t, J=8.8 Hz, 2H).

(B) N-(1-Benzylindolin-5-yl)methyl-N-hydroxyurea, 5

To a solution of the aldehyde (2, 2.75 g, 11.6 mmol) in EtOH (11.6 ml)and pyridine (11.6 ml) was added hydroxylamine hydrochloride (1.25 g,17.4 mmol) at ambient temperature. The mixture was stirred at ambienttemperature for 1.7 hr. The whole was concentrated in vacuo and theresulted residue was partitioned between ethyl acetate (50 ml) and H₂ O(20 ml). The aqueous layer was extracted with ethyl acetate (50 ml). Theorganic extracts were combined, washed with brine (50 ml×2) and driedover MgSO₄ to give light yellow solid (3, 3.71 g).

The oxime (3, 3.71 g) was dissolved in acetic acid (23.2 ml, 0.403 mol)and NaB(CN)H₃ (889mg, 13.4 mmol) was added portionwise to the solutionduring a period of 2 hr. The mixture was stirred for further 30 min,then cooled in an ice bath and neutrized with 10N-NaOH (38.2 ml, 0.382mol) and then 10% aqueous K₂ CO₃. The mixture was extracted with ethylacetate (50 ml×2) and washed with saturated NaCl solution (50 ml×2). Theorganic layer was dried over MgSO₄ and evaporated to give a yellow oil(4, 3.07 g).

To a solution of the hydroxylamine (4, 3.07 g) in dry THF (23mi) wasadded trimethylsilyl isocyanate (2.77 ml, 17.4 mmol) and the whole wasstirred overnight under nitrogen atmosphere. The mixture wasconcentrated in vacuo to give a yellow oil (4.51 g). Chromatography onsilica gel (100 g) eluted with CH₂ Cl₂ /ethyl acetate/MeOH (30:1:1) togive white solids. Recrystallization from ethyl acetate gaveN-(1-benzylindolin-5-yl)methyl-N-hydroxyurea (5, 2.26 g, 65.5%)as whitesolids. m.p.: 106.8°-107.2° C.

IR (KBr) cm⁻¹ : 3476, 3171, 2801, 1639, 1598, 1494, 1444, 1148, 1081,695.

NMR (DMSO-d₆) δ: 9.18 (d,J=2.2 Hz, 1 H),7.31-7.38(m,4H),7.22-7.30(m,1H),6.98 (s, 1H), 6.90 (d,J=7.7 Hz, 1H), 6.50 (d,J=8.1 Hz, 1H), 6.22 (s,2H), 4.35 (s, 2H), 4.24 (s, 2H), 3.23 (t,J=8.4 Hz, 2H), 2.86 (t,J=8.2Hz, 2H).

EXAMPLE 2 N-Hydroxy-N-{1-(3-phenylpropyl)indolin-5-yl}methylurea##STR7## (A) 1-(3-Phenylpropyl)indoline 6

To a solution of indoline (2.5 ml, 20 mmol) in dry toluene (5 ml) wasadded hydrocinnamoyl chloride (3.1 ml, 21 mmol) to give white solids.The mixture was stirred at reflux under a nitrogen atmosphere for 1 hr.The mixture was concentrated in vacuo to give ivory color solids. Thiswas suspended in dry tetrahydrofuran (28 ml). To the suspension wasadded BH₃.SMe₂ (3.8 ml, 40 mmol) and stirred at room temperature for 30min and then at reflux for 2 hr under a nitrogen atmosphere. To themixture was carefully added Na₂ SO₄.10H₂ O (excess), then H₂ O added.The whole was extracted with ethyl acetate (50 ml), washed with brine(10 ml), dried over MgSO₄ and concentrated in vacuo to give yellow oil(5.1 g). Chromatography on silica gel (50 g) eluted with hexane-ethylacetate (30:1) gave a colorless oil (6, 4.05 g, 85%).

NMR (CDCl₃) δ7.15-7.33 (m, 5H), 7.01-7.09 (m, 2H),6.63(t, J=7.3 Hz, 1H),6.41 (d, J=7.7 Hz, 1H), 3.34 (t, J=8.4 Hz, 2H), 3.07 (t, J=7.2 Hz, 2H),2.96 (t, J=8.2 Hz, 2H), 2.73 (t, J=7.7 Hz, 2H), 1.93 (quint, J=7.4 Hz,2H).

(B) 1-(3-Phenylpropyl)-5-formylindoline, 7

POCl₃ (2.39 ml) was added to DMF (25 ml) and the mixture was stirred atroom temperature under a nitrogen atmosphere for 1 hr. To the mixturewas added compound (6, 4.05 g, 17.1 mmol) in DMF (9 ml) and stirred atroom temperature for 2 hr. H₂ O (5 ml) was added and concentrated invacuo to give a dark green oil. The resulted residue was partitionedbetween ethyl acetate (150 ml) and H₂ O (70 ml). The aqueous layer wasextracted with ethyl acetate (50 ml). The extracts were combined, washedwith brine (30 ml), saturated NaHCO₃ solution (30 ml) and brine (30 ml).The solution was dried over MgSO₄ and concentrated in vacuo to give adark green oil. Chromatography on silica gel (50 g) eluted withhexane-ethyl acetate (5:1) gave a yellow oil (7, 3.09 g, 68.2%).

NMR (CDCl₃) δ9.65 (s, 1H), 7.50-7.57 (m, 2H), 7.16-7.34 (m, 5H), 6.28(d, J=8.8 Hz, 1H), 3.59 (t, J=8.4 Hz, 2H), 3.22 (t, J=7.3 Hz, 2H), 3.04(t, J=8.6 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 1.95 (quint, J=7.5 Hz, 2H).

(C) N-Hydroxy-N-{1-(3-phenylpropyl)indolin-5-yl}methylurea, 8

N-Hydroxy-N-{1-(3-phenylpropyl)indolin-5-yl }methylurea, 8 was preparedfrom compound 7 according to the procedure of Example 1, Part (B).

m.p.: 94.0°-94.5° C.

IR (KBr) cm⁻¹ : 3470, 3330, 3190, 2950, 2800, 1618, 1575, 1497.

NMR (DMSO-d₆) δ: 9.16 (s, 1H), 7.14-7.32 (m, 5H), 6.96 (s, 1H), 6.89 (d,J=8.1 Hz, 1H), 6.33 (d, J=8.1 Hz, 1H), 6.22 (s, 2H), 4.34 (s, 2H), 3.27(t, J=8.3 Hz, 2H), 3.01 (t, J=7.2Hz, 2H), 2.85 (t, J=8.3 Hz, 2H), 2.66(t, J=7.7 Hz, 2H), 1.83 (quint, J=7.3 Hz, 2H).

EXAMPLE 3 N-Hydroxy-N-(1-phenylindolin-5-yl)methylurea

A synthetic intermediate, N-phenylindoline was prepared by knownreaction procedures. See the following references; Gordon N. Walker,Ronald T. Smith, and Barbara N. Weaver, J. Med. Chem., 8, p. 626, 1965,Heinz Sirowej, Shafiq Ahmad Khan and Hans Plieninger, Synthesis, p. 84,1972, Bruce E. Martanoff and David F. McComsey, J. Org. Chem., 43, p.2733, 1978.

Conversion to the title compound was achieved by following the procedureof Example 1.

m.p.: 143.0°-143.3° C.

IR (KBr) cm⁻¹ : 3490, 3320, 2860, 1625, 1580, 1510, 1380, 1325. NMR(DMSO-d₆) δ: 9.23 (s, 1H), 7.34 (t, J=7.8 Hz, 2H), 7.21 (d, J=7.7 Hz,2H), 7.11 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.89-6.99 (m, 2H), 6.26 (s,2H), 4.40 (s, 2H), 3.91 (t, J=8.4 Hz, 2H), 3.06 (t, J=8.4 Hz, 2H).

The compounds of Examples 4, 5, 6, 7, 8, 9, 10 and 11 were prepared inthe same manner used for the preparation of compounds of EXAMPLE 1.

EXAMPLE 4 N- Hydroxy-N-{1-(3-methoxybenzyl)indolin-5- yl}methylurea

m.p.: 73.4°-74.5° C.

IR (KBr) cm⁻¹ : 3516, 3234, 2806, 1660, 1629, 1581, 1489, 1265, 1141,1044, 789, 765, 697, 506.

NMR (DMSO-d₆) δ: 9.05 (s, 1H), 7.13 (t, J=7.9Hz, 1H), 6.86 (s, 1H),6.74-6.83 (m, 3H), 6.71 (dd, J=8.6, 1.8 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H),6.10 (s, 2H), 4.23 (s, 2H), 4.08 (s, 2H), 3.61 (s, 3H), 3.12 (t, J=8.2Hz, 2H), 2.74 (t, J=8.2 Hz, 2H).

EXAMPLE 5N-Hydroxy-N-{1-(3-trifluoromethylbenzyl)indolin-5-yl}methylurea

m.p.: 109.3°-109.9° C.

IR (KBr)cm⁻¹ : 3500, 3242, 2847, 1640, 1575, 1500, 1454, 1352, 1327,1265, 1108, 951, 797, 700.

NMR (DMSO-d₆) δ9.19 (s, 1H), 7.55-7.79 (m, 4H), 7.01 (s, 1H), 6.91 (d,J=7.7 Hz, 1H), 6.50 (d, J=8.1 Hz, 1H), 6.24 (s, 2H), 4.37 (s, 2H), 4.34(s, 2H) 3.26 (t, J=7.9 Hz, 2H), 2.89 (t, J=7.9 Hz, 2H).

EXAMPLE 6 N-{1-(3-Cyanobenzyl)indolin-5-yl}methyl-N-hydroxyurea

m.p.: 97.1°-98.0 C.

IR (KBr) cm⁻¹ : 3500, 3345, 2829, 2224, 1644, 1574, 1492, 1249, 818,780, 683.

NMR (DMSO) δ9.19 (s, 1H), 7.79 (s, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.69 (d,J=8.1 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 6.99 (s, 1H), 6.90 (d, J=8.1 Hz,1H), 6.48 (d, J=8.1 Hz, 1H), 6.22 (s, 2H), 4.36 (s, 2H), 4.30 (s, 2H),3.26 (t, J=8.4 Hz, 2H), 2.88 (t=8.2 Hz, 2H).

EXAMPLE 7 N-{1 -(3-Fluorobenzyl)indolin-5-yl}methyl-N-hydroxyurea

m.p.: 106.2°-107.3° C.

IR (KBr)cm⁻¹ : 3435, 3202, 2855, 1673, 1586, 1507, 1450, 1341, 1262,1119, 949, 773, 681, 500.

NMR (DMSO-d ₆) δ: 9.18 (s, 1H), 7.34-7.43 (m, 1H), 7.03-7.23 (m, 3H),7.00 (s, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.48 (d, J=8.1 Hz, 1H), 6.24 (s,2H), 4.37 (s, 2H), 4.26 (s, 2H), 3.26 (t, J=8.4 Hz, 2H), 2.88 (t, J=8.2Hz, 2H).

Example 8 N-{1-(3-Chlorobenzyl)indolin-5-yl}methyl-N-hydroxyurea

m.p.: 123.6°-123.9° C.

IR (KBr) cm⁻¹ : 3500, 3186, 2858, 1638, 1571, 1500, 1462, 1352, 1245,1146, 781, 770, 692.

NMR (DMSO-d₆) δ: 9.18 (s, 1H), 7.28-7.42 (m, 4H), 7.00 (s, 1H), 6.90 (d,J=8.1 Hz, 1H), 6.48 (d, J=8.1 Hz, 1H), 6.24 (s, 2H), 4.36 (s, 2H), 4.25(s, 2H),(s, 2H), 3.26 (t, J=8.2 Hz, 2H), 2.88 (t, J=8.2 Hz, 2H).

EXAMPLE 9 N-Hydroxy-N-{1-(3-methylbenzyl)indolin-5-yl}methylurea

m.p.: 89.4°-89.8° C.

IR (KBr) cm⁻¹ : 3450, 3350, 3270, 3200, 2860, 1675, 1620, 1587, 1550,1440, 1410, 1340, 1303, 1278.

NMR (DMSO-d₆) δ: 9.16 (s, 1H), 7.22 (t, J=7.4 Hz, 1H),7.12-7.18 (m, 2H),7.09 (t, J=7.0 Hz, 1H), 6.98 (s, 1H), 6.89 (d, J=7.7 Hz, 1H), 6.48 (d,J=8.0 Hz, 1H),6.23 (s, 2H), 4.35 (s, 2H), 4.18 (s, 2H), 3.22 (t, J=8.3Hz, 2H), 2.85 (t, J=8.3 Hz, 2H), 2.29 (s, 3H).

EXAMPLE 10N-{1-(3-Difluoromethoxybenzyl)indolin-5-yl}methyl-N-hydroxyurea

m.p.: 112.0°-112.2° C.

IR (KBr)cm⁻¹ : 3500, 3230, 2847, 1639, 1570, 1500, 1454, 1351, 1245,1165, 1120, 1039, 950, 800, 780.

NMR (DMSO-d₆) δ: 9.20 (s, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.7Hz, 1H), 7.23 (t, J=74.2 Hz, 1H), 7.15 (s, 1H), 7.10 (dd, J=1.5, 8.1 Hz,1), 6.99 (s, 1H), 6.91 (dd, J=1.5, 7.7 Hz, 1H), 6.64 (d, J=8.1 Hz, 1H),6.24 (s, 2H), 4.36 (s, 2H), 4.26 (s, 2H), 3.26 (t, J=8.2 Hz, 2H), 2.88(t, J=8.2 Hz, 2H).

EXAMPLE 11 N-(1-Benzylindolin-5-yl)methyl-N'-ethyl-N-hydroxyurea

m.p.: 96.5°-97.3° C.

IR (KBr)cm⁻¹ : 3410, 2850, 1630, 1550, 1480, 1472, 1455, 1360, 1213,1117.

NMR (DMSO-d₆) δ: 9.08 (s, 1H), 7.22-7.38 (m, 5H), 6.96 (s, 1H), 6.89 (d,J=8.1 Hz, 1H),6.81 (t, J=5.7 Hz, 1H), 6.50 (d, J=8.1 Hz, 1H), 4.34 (s,2H), 4.24 (s, 2H), 3.23 (t, J=8.3 Hz, 2H), 3.01-3.12 (m, 2H), 2.85 (t,J=8.3 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H).

The compounds of Examples 12 and 13 were prepared in the same mannerused for the preparation of compounds of Example 2.

EXAMPLE 12 N-Hydroxy-N-{(1-phenoxyethyl)indolin-5-yl}methylurea

m.p.: 122.0°-122.4 C.

IR (KBr)cm⁻¹ : 3490, 3320, 2890, 2800, 1625, 1580, 1500, 1470, 1377,1245, 1080, 1053.

NMR (DMSO) δ: 9.17 (s, 1H), 7.23-7.33 (m, 2H), 6.88-7.01 (m, 5H), 6.50(d J=8.1 Hz, 1H), 6.22 (s, 2H), 4.35 (s, 2H), 4.16 (t, J=5.7 Hz, 2H),3.38-3.49 (m, 4H), 2.87 (t, J=8.2 Hz, 2H).

EXAMPLE 13N-Hydroxy-N-[1-{2-(3-methoxyphenyl)ethyl}indolin-5-yl]methylurea

m.p.: -(oil)

IR (CHCl₃) cm⁻¹ : 3550, 3420, 3010, 1675, 1565, 1495, 1440, 1260, 1155.

NMR (DMSO-d₆) δ: 9.16 (s, 1H), 7.20 (t, J=8.1 Hz, 1H), 6.96 (s, 1H),6.77 (br d, J=7.7 Hz, 1H), 6.47 (d, J=8.1 Hz, 1H), 6.22 (s, 2H), 4.34(s, 2H), 3.74 (m, 4H), 2.74-2.90 (m, 4H).

EXAMPLE 14 N-(1-Benzylindolin-5-yl)methyl-N-hydroxyacetamide ##STR8##(A) N-Acetoxy-N-{(1-benzylindolin-5-yl)methyl}acetamide, 9

To a solution of compound (4, 1.806 g, 7.11 mmol) in pyridine (3 ml) wasadded acetic anhydride (3 ml). The mixture was stirred at roomtemperature for 1 hr. The mixture was concentrated in vacuo and theresulted residue was partitioned between ethyl acetate (70 ml) and H₂ O(30 ml). The organic layer was washed with saturated NaHCO₃ solution(3×20 ml) and brine (20 ml). The solution was dried over MgSO₄ andconcentrated in vacuo. Chromatography on silica gel (40 g) eluted withhexane-ethyl acetate (2:1) gave a yellow oil (9, 1.29 g, 53.9%).

NMR (CDCl₃) δ: 7.21-7.37 (m, 5H), 7.03 (s, 1H), 6.93 (d, J=8.1 Hz, 1H),6.42 (d, J=8.1 Hz, 1H), 4.74 (s, 2H), 4.24 (s, 2H), 3.34 (t, J=8.3 Hz,2H), 2.96 (t, J=8.2 Hz, 2H), 2.12 (s, 3H), 2.04 (br s, 3H).

(B) N-(1-Benzylindolin-5-yl)methyl,N-hydroxyacetamide, 10

To a solution of compound (9, 1.29 g, 3.8 mmol) in methanol (4 ml) wasadded conc. aqueous ammonia (25%, 1.6 ml) and the mixture was stirred atroom temperature for 1 hr. The solvents were removed off and theresulted residue was extracted with ethyl acetate (50 ml). The extractswere washed with brine (2×20 ml). The solution was dried over MgSO₄ andconcentrated in vacuo. Chromatography on silica gel (30 g) eluted withhexane-ethyl acetate (2:1 -1:1) gaveN-(1-Benzylindolin-5-yl)methyl-N-hydroxyacetamide, 10 as a colorless oil(0.7 g, 62%).

NMR (DMSO-d₆) δ: 9.70 (s, 1H), 7.21-7.39 (m, 5H), 6.96 (s, 1H), 6.89 (d,J=8.1, 1H), 6.51 (d, J=8.1 Hz, 1H), 4.50 (s, 2H), 4.25 (s, 2H), 3.25 (t,J=8.2 Hz, 2H), 2.87 (t, J=8.2 Hz, 2H), 2.87 (t, J=8.2 Hz, 2H), 1.99 (s,3H).

EXAMPLE 15 N-Hydroxy-N-{1-(3-phenoxybenzyl)indolin-5-yl}methylurea

The compound of Example 15 was prepared in the same manner used for thepreparation of compound of EXAMPLE 1.

m.p.: -(oil)

IR (neat) cm⁻¹ : 3534, 3032, 1674, 1587, 1565, 1487, 1444, 1248, 1212,929, 785, 732, 669, 626.

NMR (DMSO) δ: 9.18 (s, 1H), 7.33-7.40 (m, 4H), 7.13 (t, J=7.3 Hz, 1H),6.94-7.04 (m, 4H), 6.89 (d, J=8.1 Hz, 2H), 6.48 (d, J=8.1 Hz, 1H), 6.22(s, 2H), 4.35 (s, 2H), 4.23 (s, 2H), 3.16-3.33 (m, 2H), 2.86 (t, J=7.9Hz, 2H).

EXAMPLE 16 N-Hydroxy-N-{1-(3-methoxybenzyl)indolin-4-yl}methylurea

(A) 4-Hydroxymethyl-1-(3-methoxybenzyl)indole, 13

Methyl indolin-4-carboxylate, 11 was synthesized by known procedures:see Gerald S Ponticello and John J. Baldwin, J. Org. Chem. 44 4003(1979) and Alan P. Kozikowski, Hitoshi Ishida, and Yon-Yih Chen, 45 3350(1980).

To a suspension of 60% NaH (2.33 g, 58.4 mmol) in dry THF (167 ml) wasadded dropwise a solution of methyl indolin-4-carboxylate (9.73 g, 55.6mmol) in dry ##STR9## THF (63ml) at 0° C. under nitrogen atmosphere. Themixture was stirred at ambient temperature for 30 min. under nitrogenatmosphere. To the stirred mixture was added 3-methoxybenzylchloride(8.7 ml, 58.3 mmol) and the stirring was continued under nitrogenatmosphere for 2 hr. To the mixture was added H₂ O (80 ml) and extractedwith ethyl acetate (300 ml and then 100 ml). The combined extracts werewashed with saturated aqueous NaCl(80 ml) and dried over MgSO₄ to give12 as a brown oil (16.51 g, 100%).

NMR (CDCl₃) δ: 7.88-7.94 (m, 1H), 7.24-7.30 (m, 1H), 7.20 (s, 1H),7.15-7.19 (m, 1H), 6.60-7.00 (m, 5H), 4.56 (s, 2H), 3.99 (s, 3H), 3.72(s, 3H).

To a cooled solution of the ester 12, 16.51 g, 55.6 mmol) in dry THF(167 ml) at 0° C. was added portionwise LiAlH₄ (3.15 g, 83.3 mmol). Themixture was stirred at 0° C. for 1 hr. under nitrogen atmosphere. To themixture was added Na₂ SO₄.10H₂ O and then H₂ O to afford whiteprecipitate. The whole was filtered and the resulted cake was washedwith ethyl acetate (200 ml). The filtrate and the washings were combinedand the organic layer was washed with brine (50 ml). The solution wasdried (MgSO₄) and concentrated in vacuo to give a brown oil.Chromatography on silica gel eluted with hexane-ethyl acetate (3:1 to1:1) gave an alcohol 13 as a brown oil (9.09 g, 61.2 %).

NMR (CDCl₃) δ: 7.10-7.34 (m, 5H), 6.76-6.85 (m, 2H), 6.61-6.74 (m, 2H),5.30 (s, 2H), 5.00 (s, 2H), 3.73 (s, 3H).

(B)N,O-Dibutoxycarbonyl-N-{1-(3-methoxybenzyl)indolin-4-ylmethyl}hydroxylamine,15

To a solution of the indole derivative (13, 0.529 g, 1.98 mmol) inacetic acid (5 ml) was added NaBCNH₃ (0.393 g, 5.94 mmol) at 15° C. andstirred at 15° C. for 2 hr. To the mixture was added H₂ O (20 ml) andthe cooled mixture at 0° C. was neutralized with 1N NaOH solution. Thewhole was extracted with CH₂ Cl₂ (50 ml) and the extract was washed withbrine (20 ml), dried (MgSO₄) and concentrated in vacuo to give aindoline derivative 14 as a pale yellow oil.

NMR (CDCl₃) δ: 7.20-7.29 (m, 2H), 7.03-7.12 (m, 1H), 6.89-6.97 (m, 2H),6.78-6.85 (m, 1H), 6.68 (d, J=7.7 Hz, 1H), 6.45 (d, J=7.7 Hz, 1H), 4.59(s, 2H), 4.22 (s, 2H), 3.78 (s, 3H), 3.35 (t, J=8.4 Hz, 2H), 2.98 (t,J=8.4 Hz, 2H).

To a solution of the alcohol (14, 0.45 g, 1.67 mmol), Ph₃ P (0.59 g,2.17 mmol) and BocNHOBoc (0.411 g, 1.75 mmol) in dry THF (3.5 ml) wasadded diethyl azodicarboxylate (0.34 ml, 2.2 mmol) at -70° C. undernitrogen atmosphere. The mixture was stirred at ambient temperatureunder nitrogen atmosphere overnight. The whole was concentrated in vacuoand the resulted triphenyl phosphine oxide was crystallized fromhexane-ethyl acetate (3:1) and removed by suction filtration. Thefiltrate was concentrated in vacuo to give a pale yellow oil (1.579 g).Chromatography on silica gel eluted with hexane-ethyl acetate 5:1 to2:1) gave 15 as a pale yellow oil (660 mg, 81.5% ).

NMR (CDCl₃) δ: 7.19-7.25 (m, 1H), 7.03 (t, J=7.5 Hz, 1H), 6.88-6.97(m,2H), 6.78-6.85 (m, 1H), 6.65 (d, J=7.5 Hz, 1H), 6.43 (d, J=7.5 Hz, 1H),4.68 (br s, 2H), 4.23 (s, 2H), 3.80 (s, 3H), 3.34 (t, J=7.7 Hz, 2H),3.00 (t, J=7.7 Hz 2H), 1.49 (s, 9H), 1.45 (s, 9H).

(C) N-Hydroxy-N-{1-(3-methoxybenzyl)indoline-4-yl}methylurea, 17

To a solution of compound (15, 0.582 g, 1.2 mmol) in CH₂ Cl₂ (12 ml) wasadded trifluoroacetic acid (2.4 ml) and stirred at ambient temperatureunder nitrogen atmosphere for 2 hr. To the mixture was added NaHCO₃solution (10 ml) and extracted with ethyl acetate (50 ml×2). Thecombined extracts were washed with brine (30 ml), dried (MgSO₄) andconcentrated in vacuo to give hydroxylamine 16 as a pale yellow oil (292mg, 86.2% ).

NMR (CDCl₃) δ: 7.20-7.29 (m, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.87-6.96 (m,2H), 6.77-6.84 (m, 1H), 6.64 (d, J=7.7 Hz, 1H), 6.44 (d, J=7.7 Hz, 1H),4.21 (s, 2H), 3.79 (s, 3H), 3.34 (t, J=8.2 Hz, 2H), 3.00 (t, J=8.2 Hz,2H).

To a solution of the hydroxylamine (16, 292 mg, 1.03 mmol) in dry THF(2.1 ml) was added trimethylisocyanate (0.25 ml, 1.57 mmol). The mixturewas stirred at ambient temperature under nitrogen atmosphere for 30 min.The whole was concentrated in vacuo and purified by silica gelchromatography eluted with CH₂ Cl₂ : MeOH: ethyl acetate=15:1:1 to10:1:1) to give white solids. Recrystallization from ethyl acetate-MeOHgave the title compound 17 as a white powder (44.6 mg, 13.2%).

m.p.: 134.4°-135.0 ° C.

IR (KBr) cm⁻¹ : 3470, 3340, 3251, 1635, 1587, 1448, 1273, 1140, 1052,769, 752, 693, 608, 524.

NMR (DMSO) δ: 9.25 (s, 1H), 7.25 (t, J=8.1 Hz, 1H), 6.93 (t, J=8.1 Hz,1H), 6.92 (d, J=8.1 Hz, 1H), 6.89 (s, 1H), 6.80-6.86 (m, 1H), 6.55 (d,J=7.0 Hz, 1H), 6.46 (d, J=7.7 Hz, 1H), 6.27 (s, 2H), 4.41 (s, 2H), 4.22(s, 2H), 3.24-3.30 (m, 2H), 2.90 (t=8.2 Hz, 2H).

EXAMPLE 17N-Hydroxy-N-[1-{1-(3-methoxybenzyl)indolin-5-yl}ethan-1-yl]urea##STR10## 5-(1-Hydroxyethyl)-1-(3-methoxybenzyl)indoline 19

An intermediate of 18 was synthesized in the same manner used for thepreparation of compound of Example 1.

To a solution of aldehyde (18, 20.05 g, 75 mmol) in dry THF (200 ml) wasadded 3.0 M MeMgBr at 0° C. under nitrogen atmosphere. The mixture wasstirred at ambient temperature for 30 min. To the mixture was added iceand then hexane (200 ml). The organic layer was washed with brine, dried(MgSO₄) and concentrated in vacuo to give a brown oil (18.9 g).Chromatography on silica gel eluted with hexane: ethyl acetate =2:1 to3:2) gave an light yellow oil (19, 19.61 g, 92.3%).

NMR (CDCl₃) δ: 7.21-7.28 (m, 1H), 7.15 (s, 1H), 7.05 (d, J=7.7 Hz, 1H),6.94 (d, J=7.7 Hz, 1H), 6.93 (s, 1H), 6.79-6.85 (m, 1H), 6.45 (d, J=8.1Hz, 1H), 4.78-4.82 (m, 1H), 4.21 (s, 2H), 3.80 (s, 3H), 3.33 (t, J=8.4Hz, 2H), 2.97 (t, J=8.2 Hz, 2H), 1.65 (d, J=3.3 Hz, 1H), 1.47, (d, J=6.2Hz, 3H).

The alcohol 19 was converted to the title compound 20 in the same mannerused for the preparation of compound of Example 16.

m.p.: 81.3°-83.6° C.

IR (KBr) cm⁻¹ : 3462, 3194, 1656, 1600, 1569, 1471, 1448, 1263, 1224,1148, 1039, 810, 768.

NMR (DMSO) δ: 8.90 (s, 1H), 7.25 (t, J=7.7 Hz, 1H), 7.06 (s, 1H), 6.97(d, J=8.1 Hz, 1H), 6.94 (d, J=7.0, 1H), 6.92 (s, 1H), 6.85 (d, J=7.8 Hz,1H), 6.49 (d, J=8.4 Hz, 1H), 6.20 (s, 2H), 5.20 (q, J=7.0 Hz, 1H), 4.22(s, 2H), 3.75 (s, 3H), 3.26 (s, 3H), 3.26 (t, J=8.4 Hz, 2H), 2.88 (t,J=8.2 Hz, 2H), 1.36 (d, J=6.9 Hz, 3H).

EXAMPLE 18N-Hydroxy-N-[4-{1-(3-methoxybenzyl)indolin-5-yl}butan-2-yl]urea

A mixture of the aldehyde (18, 5.76 g, 21.6 mmol) and1-triphenylphosphoranylidene-2-propanone (8.28 g, 26 mmol) in drytoluene (26 ml) was stirred at reflux for 4 hr. The mixture wasconcentrated in vacuo and purified by silica gel column (100 g) elutedwith hexane-ethyl acetate (2:1) gave an yellow oil which wascrystallized from hexane gave yellow solids 21(6.04 g, 91%)

NMR (CDCl₃) δ: 7.44 (d, J=16.1 Hz, 1H), 7.21-7.34(m, 3H), 6.79-6.91 (m,3H), 6.51(d, J=16.1 Hz, 1H), 6.43 (d, J=8.1 Hz, 1H), 4.32 (s, 2H), 3.79(s, 3H), 3.49 (t, J=8.6 Hz, 2H), 3.03 (t, J=8.4 Hz, 2H), 2.33 (s, 3H).##STR11##

A solution of the conjugated ketone (21, 0.601 g, 1.95 mmol) in ethanol(20 ml) was hydrogenated at 25° C. and 3 atm over 5% Pd on carbon (98mg) for 3 hr. The whole was filtered through celite and the celite cakewas washed with ethanol (80 ml). The filtrate and washings were combinedand concentrated in vacuo to give an yellow oil. Chromatography onsilica gel eluted with hexane: ethyl acetate=4:1 to 2:1 gave a paleyellow oil (22, 480 mg, 79.6%).

NMR (CDCl₃) δ: 7.24 (t, J=7.9 Hz, 1H), 6.92-6.98 (m, 3H), 6.77-6.89 (m,2H), 6.42 (d, J=8.1 Hz, 1H), 4.18 (s, 2H), 3.80 (s, 3H), 3.29 (t, J=8.2Hz, 2H), 3.93 (t, J=8.2 Hz, 2H), 2.79 (td, J=2.6, 7.0 Hz, 2H), 2.71 (td,J=3.7, 7.0 Hz, 2H), 2.13 (s, 3H).

The ketone 22 was converted to the title compound 23 in the same mannerused for the preparation of compounds of Example 1.

m.p.: 142.3°-143.2° C.

IR (KBr)cm ⁻¹ : 3474, 3356, 3170, 1652, 1458, 1440, 1274.

NMR (DMSO) δ: 8.88 (s, 1H), 7.30 (t, J=7.7 Hz, 1H), 6.94-6.98 (m, 3H),6.88 (d, J=7.3 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.51 (d, J=8.1 Hz, 1H),6.28 (s, 2H), 4.22 (s, 2H), 4.12 (q, J=6.6 Hz, 1H), 3.78 (s, 3H), 3.25(t, J=8.1 Hz, 2H), 2.89 (t=8.2 Hz, 2H), 1.02 (d, J=6.6 Hz, 3H).

We claim:
 1. A compound of the following chemical formula orpharmaceutically acceptable salt thereof; ##STR12## wherein R₁ is C₁ -C₄alkyl or --NR₂ R₃ ; R₂ and R₃ are each, independently, hydrogen or C₁-C₄ alkyl;R₄ is C₃ -C₆ cycloalkyl, C₄ -C₇ cycloalkylalkyl, aryloxy C₂-C₄ alkyl, arylthio C₂ -C₄ alkyl, arylamino C₂ -C₄ alkyl, arylsulfinylC₂ -C₄ alkyl, aryl, aryl C₁ -C₆ alkyl, aryloxyary C₁ -C₆ alkyl orarylthioaryl C₁ -C₆ alkyl, and the aryl groups in the said aryloxyalkyl,arylthioalkyl, arylaminoalkyl, arylsulfinylalkyl, aryl, arylalkyl,aryloxyarylalkyl and arylthioalkyl may be substituted with from 1 to 7substituents and the substituents are each, independently, selected fromthe group consisting of halo, cyano, C₁ -C₅ alkyl, C₂ -C₆ alkenyl, C₁-C₅ alkoxy, C₂ -C₆ alkenyloxy, C₂ -C₆ alkoxyalkyl, halosubstituted C₁-C₄ alkyl, halosubstituted C₁ -C₄ alkoxy, C₂ -C₅ alkoxycarbonyl,aminocarbonyl and C₁ -C₄ alkylthio; A is C₁ -C₆ alkylene, C₃ -C₆alkenylene or --O--(CH₂)_(m) --; Y is each, independently, halogen,halosubstituted C₁ -C₆ alkyl, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₁ -C₆alkoxy or C₃ -C₈ alkenyloxy; m is 2, 3 or 4; n is 0, 1, 2 or 3;andprovided that the substituent Y, if present, and the linking group A areattached to the aromatic ring.
 2. A compound according to claim 1,wherein R₁ is --NH₂ ;R₄ is phenyl, phenoxy C₂ -C₄ alkyl, phenyl C₁ -C₆alkyl, phenoxyphenyl C₁ -C₆ alkyl, mono-substituted phenyl ormono-substituted phenyl C₁ -C₆ alkyl, wherein the substituent is halo,cyano, C₁ -C₅ alkyl, C₁ -C₅ alkoxy, CF₃ or OCF₂ ; A is alkylene and n is0.
 3. A compound according to claim 2, wherein R₄ is phenyl, benzyl,3-phenylpropyl, mono-substituted phenyl, mono-substituted benzyl ormono-substituted 3-phenylpropyl.
 4. A compound according to claim 3wherein R₄ is phenyl, benzyl or methoxybenzyl. 5.N-(1-Benzylindolin-5-yl)methyl-N-hydroxyurea. 6.N-Hydroxy-N-{1-(3-methoxybenzyl)indolin-5-yl}methylurea. 7.N-Hydroxy-N-(1-phenylindolin-5-yl)methylurea.
 8. A pharmaceuticalcomposition for the treatment of allergic or inflammatory conditions ina mammalian subject which comprises a therapeutically effective amountof a compound of claim 1 and its pharmaceutically acceptable carrier.